Coinfection

Over the past several years, there have been increasing reports of outbreaks of acute hepatitis C virus (HCV) infection among HIV positive men who have sex with men (MSM). Acute HCV is the initial 6-month period of newly acquired HCV infection.

In the current study, published in the July 15, 2008 online edition of the Journal of Infectious Diseases, Daniel Fierer from the Mount Sinai School of Medicine in New York City and colleagues evaluated risk factors and liver histopathology of 11 consecutively enrolled HIV positive men with recently acquired HCV infection.

Fierer first reported at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) in Los Angeles that several HIV positive MSM with acute hepatitis C showed evidence of severe liver fibrosis, which typically develops much later in the course of HCV infection. He followed up with additional similar findings at the 2008 CROI in Boston.

The recently published report extends the data further.

Results

11 MSM with asymptomatic, sexually-acquired HIV infection of 11 months to 16 years duration were found during routine medical visits to have elevated transaminase levels, which led to further testing and the clinical diagnosis of acute HCV infection.

In all these patients, acute hepatitis A virus infection was excluded serologically and acute and chronic HBV infection were included both serologically and by HBV DNA testing.

Patients 1, 3, and 6 reported a single recent episode of injecting methamphetamine; 1 remembered sharing injection equipment, but the others had no recollection of doing so.

Patients 2, 6, and 11 had shared paraphernalia used for snorting drugs on multiple occasions with other MSM.

Patient 4 had a possible percutaneous exposure.

5 men denied any parenteral risk factors or “club drug” use.

Discussion

According to the investigators, immunosuppression increases the progression of fibrosis in HCV-infected patients. “The magnitude of the acceleration is relatively modest if immunosuppression occurs after the chronic phase of HCV infection has been established,” they wrote.

The authors pointed out that prior study results have indicated that the fibrosis progression rate (FPR) of patients with chronic HCV monoinfection is 0.11 unts per year and that the FPR of patients with chronic HIV-HCV coinfection is <2-fold greater, at 0.15 units per year.

“The majority of HIV-HCV coinfected injection drug users (IDUs) are not expected to develop cirrhosis (stage 4 fibrosis) for 20 years or more,” wrote the researchers. In contrast, they noted, “Patients who acquire HCV infection when they already have defects in cellular immunity are reported to progress to cirrhosis, end-stage liver disease, and death in as few as 3 years.

They continued, “This dire outcome has been observed in transplant recipients, patients with hematological disorders and immunodeficiencies, and patients with preexisting HIV infection.”

Among the 11 consecutive HIV-infected MSM in the study who underwent liver biopsy during the early periods of HCV infection, nine (82%) had stage 2 fibrosis. In contrast, biopsy specimens from immunocompetent patients obtained during the early periods of HCV infection contained no or minimal fibrosis [1].

“[Therefore] the FPR of the HIV-infected MSM with newly acquired HCV infection in our study was far higher than that of immunocompetent patients with acute HCV infection,” wrote the authors.

“Our findings of moderately advanced fibrosis during the initial period of HCV infection are consistent with the rapid clinical progression to end-stage liver disease reported in previous studies of individuals who acquired HCV infection while already infected with HIV or who acquired HIV and HCV infection simultaneously.”

In their conclusion, the researchers stated that their study indicates that high-risk sexual practices and non injection-drug use may play a role in the transmission of HCV to HIV-infected MSM.

In addition, they wrote, “Our findings also demonstrate that HIV-infected men with acute HCV infection have moderately advanced liver disease. The FPR of this population is 5 times greater than that for people who are not immunocompromised at the time when they become HCV infected. Our findings are of particular importance with regard to the recent outbreaks of acute HCV infection in HIV-infected MSM in Europe and the United States” [2].

The authors observed that regular screening of MSM for HCV antibodies “is not currently recommended by U.S. or international HIV care guidelines, and ALT elevations during acute HCV infection are relatively transient and therefore could be easily missed during routine clinical care.” They maintained that many (if not most) cases of acute HCV infection “are not diagnosed, even in areas in which the outbreaks have been recognized.”

In closing, the study authors urge caregivers to initiate more intensive screening of HIV-infected MSM, “given the grave implications of missing the diagnosis of acute HCV infection in these patients.”

Divisions of Infectious Diseases and Liver Diseases, Department of Medicine, and Department of Pathology, Mount Sinai School of Medicine, New York, NY.

Research has shown that HIV positive people with hepatitis C virus (HCV) coinfection tend to respond less well to interferon-based therapy, but the factors that predict favorable response are generally similar. The objective of the current study, published in the August 2008 issue of the Journal of Viral Hepatitis, was to evaluate the role of rapid virological response in predicting sustained virological response to anti-HCV therapy.

Multiple outbreaks of acute hepatitis C virus (HCV) infection have recently been reported in cities in the UK and Europe among HIV positive men who have sex with men (MSM). These outbreaks are notable because these patients were already infected with HIV when they acquired HCV. More typically, individuals with both HIV and HCV infection acquired HCV first, since it is easier to transmit (e.g., through shared use of injection drug equipment).

Although much is known about the course of liver disease in HCV-infected patients who later acquire HIV, little is known about the course of liver damage in HIV-infected patients who later acquire HCV.

Researchers at Mount Sinai School of Medicine in New York City conducted a prospective study of HIV-infected MSM with acute HCV infection, including examination of liver histology. At the 14th Conference on Retroviruses and Opportunistic Infections last month in Los Angeles,they reported data from the first 5 consecutively-enrolled patients.

Acute hepatitis C was defined as the first 6 months of HCV infection. Because no single test result provides a definitive diagnosis of acute HCV infection, the researchers considered 3 factors in combination:

Recent seroconversion to HCV antibody positive status;

Marked elevations in serum ALT level;

Wide fluctuations in HCV viral load.

The latter 2 factors are considered hallmarks of acute HCV infection and are uncommon during chronic infection.

All patients were MSM in their 40s who had:

Recent seroconversion to anti-HCV antibody positive status; in 3 cases, this occurred within a year after a previous negative test, defining a narrow time window in which the new HCV infection could have occurred;

Rapid changes in ALT levels, with elevations greater than 10 times the upper limit of normal (ULN), consistent with acute hepatitis;

Liver biopsies showed moderate portal fibrosis (stage 2 of 4; Scheuer system) in 3 of 4 patients [SHOULD THIS BE 4 OF 5?], as well as acute HCV.

1 patient had central hyalin sclerosis.

All patients denied heavy alcohol use and 1 had never received HAART.

No cause of chronic liver disease common to all patients could be identified to explain the degree of fibrosis.

All had negative evaluations for active HAV or HBV infection.

No evidence for other etiologies of new hepatitis was found.

All patients had recent histories of unprotected receptive anal intercourse, some with many partners;

3 acknowledged a single recent episode of injection drug use, but without clear recollection of sharing injection equipment.

1 shared paraphernalia for snorting drugs;

All denied any other known risk factors for HCV infection.

Conclusions

The researchers concluded that 4 of 5 HIV-infected MSM had moderately advanced portal fibrosis during the acute phase of HCV infection. No other etiologies were found to explain the presence of moderate liver fibrosis in this population, suggesting that pre-existing HIV infection results in accelerated fibrosis progression in patients with acute hepatitis C.

The investigators noted that, “These cases suggest that HIV-infected patients presenting with acute HCV infection may already have significant liver disease, and that liver biopsy should be considered in theses patients."

They added that further research is needed to define the prevalence and understand the pathogenesis of rapid liver fibrosis in this population.

Since the advent of effective antiretroviral therapy has reduced the rate of death due to opportunistic illnesses and other AIDS-related causes, liver disease has emerged as a major cause of death among HIV positive people. HIV, in turn, has also influenced rates of death among patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, according to a study published in the February 2008 Journal of Hepatology.

In this analysis, Patrick Marcellin and colleagues estimated mortality related to HCV and HBV infection in France. A random sample of 999 death certificates was obtained from among all 65,000 French death certificates in 2001 that listed HBV, HCV, hepatitis, liver disease, possible complication of cirrhosis, bacterial infection, HIV, or transplantation as causes of death. Physicians who reported these deaths were sent a questionnaire to identify how many deaths were related to HBV or HCV infection. Death rates were then estimated according to national population census data.

Results

• The estimated annual number of deaths associated with HCV was 3618 (6.1 deaths per 100,000 inhabitants).

• The estimated annual number of deaths associated with HBV was 1507 (2.5 per 100,000 inhabitants).

• The estimated number of deaths attributable to HCV was 2646 (4.5 per 100,000 inhabitants).

• The estimated number of deaths attributable to HBV was 1327 (2.2 per 100,000 inhabitants).

• In the HCV infected group, 95% had cirrhosis and 33% had hepatocellular carcinoma (HCC).

• In the HBV infected group, the rates were similar: 93% and 35%, respectively.

• 11% percent of these deaths occurred in patients with HIV coinfection.

• Deaths related to hepatitis B or C occurred at an earlier age in patients with a history of excessive alcohol consumption.

Multiple outbreaks of acute hepatitis C virus (HCV) infection have recently been reported in cities in the UK and Europe among HIV positive men who have sex with men (MSM). These outbreaks are notable because these patients were already infected with HIV when they acquired HCV. More typically, individuals with both HIV and HCV infection acquired HCV first, since it is easier to transmit (e.g., through shared use of injection drug equipment).

Although much is known about the course of liver disease in HCV-infected patients who later acquire HIV, little is known about the course of liver damage in HIV-infected patients who later acquire HCV.

Researchers at Mount Sinai School of Medicine in New York City conducted a prospective study of HIV-infected MSM with acute HCV infection, including examination of liver histology. At the 14th Conference on Retroviruses and Opportunistic Infections last month in Los Angeles, they reported data from the first 5 consecutively-enrolled patients.

Acute hepatitis C was defined as the first 6 months of HCV infection. Because no single test result provides a definitive diagnosis of acute HCV infection, the researchers considered 3 factors in combination:

Recent seroconversion to HCV antibody positive status;

Marked elevations in serum ALT level;

Wide fluctuations in HCV viral load.

The latter 2 factors are considered hallmarks of acute HCV infection and are uncommon during chronic infection.

All patients were MSM in their 40s who had:

Recent seroconversion to anti-HCV antibody positive status; in 3 cases, this occurred within a year after a previous negative test, defining a narrow time window in which the new HCV infection could have occurred;

Rapid changes in ALT levels, with elevations greater than 10 times the upper limit of normal (ULN), consistent with acute hepatitis;

No cause of chronic liver disease common to all patients could be identified to explain the degree of fibrosis.

All had negative evaluations for active HAV or HBV infection.

No evidence for other etiologies of new hepatitis was found.

All patients had recent histories of unprotected receptive anal intercourse, some with many partners.

3 acknowledged a single recent episode of injection drug use, but without clear recollection of sharing injection equipment.

1 shared paraphernalia for snorting drugs.

All denied any other known risk factors for HCV infection.

The researchers concluded that 4 of 5 HIV-infected MSM had moderately advanced portal fibrosis during the acute phase of HCV infection. No other etiologies were found to explain the presence of moderate liver fibrosis in this population, suggesting that pre-existing HIV infection results in accelerated fibrosis progression in patients with acute hepatitis C.

The investigators noted that, “These cases suggest that HIV-infected patients presenting with acute HCV infection may already have significant liver disease, and that liver biopsy should be considered in theses patients.”

They added that further research is needed to define the prevalence and understand the pathogenesis of rapid liver fibrosis in this population.

In recent years there have been reports of several outbreaks of apparently sexually transmitted acute hepatitis C among mostly HIV positive men who have sex with men (MSM) in European cities and Australia. These cases are notable because the patients were known to already be infected with HIV when they acquired HCV (typically HCV is acquired first).

Several studies have shown that HIV-HCV coinfected individuals with chronic hepatitis C tend to experience more rapid liver fibrosis progression. But little is known about the effect of HIV on liver disease in people with acute HCV infection.

At the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) last February, Daniel Fierer and colleagues from Mt. Sinai School of Medicine in New York City presented early data from a prospective study of HIV positive MSM with acute HCV infection, defined as the first 6 months after HCV infection. The researchers considered a combination of 3 criteria as indicators of acute hepatitis C: recent seroconversion to HCV antibody positive status, marked elevations in serum alanine aminotransferase (ALT) level, and wide fluctuations in HCV viral load.

Study participants underwent liver biopsy within 4 months of the first-noted ALT elevation. Fibrosis was staged using the Scheuer system, on a scale of 0 to 4. Fibrosis progression rate (FPR) was calculated by dividing the fibrosis stage by the interval between the dates of the recent ALT elevation and the biopsy.

As previously reported, among the first 5 enrolled patients, 4 already had moderate portal fibrosis during acute hepatitis C. At this year’s CROI, taking place this week in Boston, the researchers presented a poster describing further data from more study participants.

Results

Of the 11 patients who underwent liver biopsy, 9 did so within 4.5 months of detection of ALT elevation, and 2 within 16 months.

Despite the short duration of HCV infection, 9 of the 11 (82%) had stage 2 fibrosis and 1 had stage 1 fibrosis.

The mean FPR in these 11 patients was 4.5 (± 3.3) units per year.

No causes of liver damage other than acute HCV infection were identified.

In the analysis of risk factors for HCV acquisition, only 4 patients reported even a single episode of intravenous drug use.

However, non-injection drug use and high-risk sexual behavior were common.

Based on these findings, the researchers concluded, “Acute HCV infection of MSM with underlying HIV infection resulted in early and rapid progression of liver fibrosis, with FPR rates far in excess of other settings of HCV infection.”

“Many of these HIV-infected men with acute HCV used non-injection drugs and had unprotected sex with multiple partners,” they continued. “Some appear to have become HCV-infected via sexual activity.”

The investigators recommended that, “More intensive prevention and screening strategies for acute HCV in MSM are needed,” and “further research is needed to identify the disease processes leading to this highly accelerated liver injury.”

In recent years, outbreaks of apparently sexually transmitted hepatitis C virus (HCV) infection have been reported in London and Brighton in the UK and in a few European cities. In almost all cases, these acute HCV infections have occurred in HIV positive gay and bisexual men.

Although results have not been not entirely consistent, several studies have shown that HIV-HCV coinfected patients tend to experience more rapid liver disease progression than HIV negative people with hepatitis C alone. A study reported in the January 11, 2008 issue of AIDS suggests a possible mechanism underlying accelerated liver disease progression in coinfected individuals.